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1.
Med Clin North Am ; 103(6): 1005-1019, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582001

RESUMO

Heritable thoracic aortic disease (HTAD) can have life-threatening consequences if not diagnosed early. Affected individuals and at-risk family members benefit from both cardiology and genetic evaluations, including genetic testing. Important information can be obtained through family history, medical history, and genetic testing to help guide management and assess risk. A genetic diagnosis can guide cardiovascular management (type and frequency of vascular imaging, timing of surgical intervention), risk assessment for arterial aneurysm/dissection, evaluation of nonvascular features, and familial testing.


Assuntos
Aorta Torácica/anormalidades , Doenças da Aorta , Testes Genéticos/métodos , Administração dos Cuidados ao Paciente/métodos , Doenças da Aorta/genética , Doenças da Aorta/terapia , Humanos , Medicina de Precisão/métodos
2.
Med Clin North Am ; 103(6): 1035-1054, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582003

RESUMO

Neurofibromatosis type 1 (NF1), NF2, and schwannomatosis are related, but distinct, tumor suppressor syndromes characterized by a predilection for tumors in the central and peripheral nervous systems. NF1 is one of the most common autosomal dominant conditions of the nervous system. NF1 has a high degree of variability in clinical presentation, which may include multiple neoplasms as well as cutaneous, vascular, bony, and cognitive features. Some of these manifestations overlap with other genetic conditions. Accurate diagnosis of NF1 is important for individualizing clinical care and genetic counseling. This article summarizes the clinical features, diagnostic work-up, and management of NF1.


Assuntos
Testes Genéticos/métodos , Neurilemoma/diagnóstico , Neurofibromatoses/diagnóstico , Neurofibromatose 1 , Neoplasias Cutâneas/diagnóstico , Diagnóstico Diferencial , Gerenciamento Clínico , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/terapia
3.
Med Clin North Am ; 103(6): 1055-1075, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582004

RESUMO

This article presents a nongeneticist's guide to understanding the genetics of Parkinson disease (PD), including clinical diagnostic criteria, differential diagnoses, symptom management, when to suspect a hereditary factor, a summary of autosomal dominant and recessive PD genes, and proposed algorithm for genetic testing. There is increasing availability of genetic testing for PD but there are few recommendations on how these tests should be used in clinical practice. This article guides clinicians on the overall management of patients with PD, with emphasis on determining which patients should have genetic testing and how to interpret the results.


Assuntos
Testes Genéticos/métodos , Doença de Parkinson , Algoritmos , Gerenciamento Clínico , Predisposição Genética para Doença , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/terapia
4.
Med Clin North Am ; 103(6): 1077-1092, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582005

RESUMO

Compared to clinicians previously surveyed, primary care providers employed in a health system known for clinical genomics were more likely to have ordered or referred a patient for genetic testing, but had only modestly more genetics training and reported similarly low levels of comfort answering patient questions about genetic risk. Most supported population genomic screening, reported willingness to get screened themselves, and judged a hypothetical patient's decision to be screened favorably relative to a similar patient's decision to decline screening. Stakeholder perceptions of the ethical appropriateness of nudging at-risk patients to discuss testing with counselors were mixed.


Assuntos
Aconselhamento Genético , Testes Genéticos/métodos , Atenção Primária à Saúde , Aconselhamento Genético/ética , Aconselhamento Genético/métodos , Aconselhamento Genético/psicologia , Humanos , Medicina de Precisão/métodos , Atenção Primária à Saúde/métodos , Atenção Primária à Saúde/tendências , Sequenciamento Completo do Exoma
5.
Med Clin North Am ; 103(6): 957-966, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582006

RESUMO

The collection of family history has always been a tool for genetic evaluation, but it remains an essential tool even in the age of genomic medicine. Patients may have a risk for a disease based on family history regardless of the results of genetic and genomic tests. How this information is collected is less important than that relevant information is collected in the first place. There are many tools for collecting medical and family history information both by hand and electronically. Genetic and genomic testing should always be interpreted in the context of the personal and family history.


Assuntos
Testes Genéticos/métodos , Anamnese/métodos , Medicina de Precisão , Humanos , Linhagem , Medição de Risco
6.
Medicine (Baltimore) ; 98(39): e17305, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574858

RESUMO

Until now, the recognition of sodium taurocholate cotransporting polypeptide (NTCP) deficiency has been mainly based on sporadic case reports. It was previously believed to be mildly symptomatic and resulting in mild liver dysfunction. However, to our knowledge, there have been no reports about the histopathologic and ultrastructural pathologic characteristics of the disease. The aim of the study was to analyze the clinical, histopathologic and ultrastructural pathologic characteristics of NTCP deficiency in 13 pediatric patients.From August 2012 to October 2018, this retrospective study conducted in the Department of Pediatrics of Tongji Hospital, China analyzed the data of 13 NTCP deficient patients with an SLC10A1 gene mutation. Except for NTCP deficiency, no other liver diseases were present in the patients, which was determined by both a genetic testing panel for jaundice and by reviewing medical records. The laboratory results, imaging, histopathologic, and ultrastructural pathologic information were recorded for analysis.The serum level of total bile acid was high in all 13 patients. All patients had adequate growth and development. Eight of the patients (8/13) presented with visible jaundice and 12 (12/13) were found to have hyperbilirubinemia. A needle liver biopsy was performed in 11 cases, which revealed slightly chronic inflammation in all 11 patients. One of the patients (1/13) was found to be suffering from gallstones.The data showed that although NTCP deficiency was often asymptomatic, some of the patients showed obvious clinical expressions, such as jaundice. Among the 13 pediatric patients with NTCP deficiency, both the biochemical and histopathologic features were similar to those of mild hepatocellular jaundice. In addition, it was determined that the clinical features in the patient with gallstones may have been caused by NTCP deficiency.


Assuntos
Ácidos e Sais Biliares/sangue , Icterícia , Hepatopatias , Fígado , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Desenvolvimento Infantil , Pré-Escolar , China/epidemiologia , Testes Genéticos/métodos , Humanos , Biópsia Guiada por Imagem/métodos , Lactente , Icterícia/diagnóstico , Icterícia/etiologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/diagnóstico , Hepatopatias/genética , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Testes de Função Hepática/métodos , Glicoproteínas de Membrana/metabolismo , Mutação , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Pediatria/métodos , Estudos Retrospectivos , Simportadores/deficiência , Simportadores/genética
7.
Rev Med Suisse ; 15(668): 1909-1913, 2019 Oct 23.
Artigo em Francês | MEDLINE | ID: mdl-31643150

RESUMO

In Switzerland, since modifications of the law regulating reproductive medicine introduced the 1rst of September 2017, preimplantation genetic testing (PGT) has been legalised. Infertile couples undergoing in vitro fertilization (IVF) can benefit from this technology by detecting which embryos are aneuploid (ie abnormal number of chromosomes, PGT-A). This is performed in order to transfer euploid embryos (normal number of chromosomes) and to optimise success, though data are limited. Couples at risk of transmitting a severe monogenic disease or unbalanced translocation can undergo PGT for monogenic disease or chromosomal structural rearrangements (PGT-M/SR). These tests are subject to strict legal criteria. Their clinical application needs to be approved through a multidisciplinary approach taking into account legal and ethical issues while respecting the autonomy of the couples.


Assuntos
Testes Genéticos/ética , Testes Genéticos/legislação & jurisprudência , Diagnóstico Pré-Implantação/ética , Aneuploidia , Feminino , Fertilização In Vitro , Testes Genéticos/métodos , Humanos , Masculino , Gravidez , Diagnóstico Pré-Implantação/métodos , Suíça
8.
Orv Hetil ; 160(36): 1417-1425, 2019 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-31492087

RESUMO

Introduction: Twenty-five percent of fine-needle aspiration biopsy samples of thyroid nodules produce indeterminate cytological results. Genetic testing of nodules can contribute to accurate diagnosis. Aim: Developing the first gene panel in Europe utilizing the 23 most relevant thyroid oncogenes with 568 mutations. Method: Examination of the isolated DNA from biopsy samples by Ion Torrent new generation sequencing. Results: The validation of our method was performed on tumor tissue samples, in which 127 genetic variations were identified, yet unknown in thyroid tumors. AXIN1 was the most polymorphic gene, while BRAF c.1799T>A (V600E) was the most frequently identified mutation. We detected 36 clinically relevant variants, 75% of which have not been described in the literature. Six of our 8 cytologically malignant and 8 of our 14 indeterminate as well as 20 of our 28 cytologically benign samples were identified as containing pathologic variants in a driver gene (BRAF c.1799T>A, NRAS c.181C>A). Conclusion: We have developed a validated, reliable new generation sequencing-based method with high positive predictive value (89%) and sensitivity (79%), suitable for the early detection of malignant lesions in the thyroid. Orv Hetil. 2019; 160(36): 1417-1425.


Assuntos
Testes Genéticos/métodos , Patologia Molecular/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Biópsia por Agulha Fina/métodos , Análise Mutacional de DNA , Europa (Continente) , Humanos , Mutação , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/patologia
9.
Int Heart J ; 60(5): 1196-1200, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484862

RESUMO

Malignant arrhythmia is a fast cardiac arrhythmia that can lead to a hemodynamic abnormality within a short time, most of which is ventricular tachycardia or ventricular fibrillation (VF), which should be managed in time. Both organic and nonorganic cardiac diseases have the potential to cause malignant arrhythmia. We report a noteworthy case of malignant arrhythmia in a teenager during exercise. Transthoracic echocardiography, cardiac magnetic resonance (CMR), electrophysiological study, magnetic resonance imaging of the brain, electroencephalography, chest X-ray, and blood tests were all normal. Twelve-lead electrocardiography showed incomplete right bundle branch block (IRBBB). Two heterozygous missense variants of the desmocollin-2 gene (DSC2, c.G2446A/p.V816M) and desmoplakin gene (DSP, c.G3620A/p.R1207K) were detected in the peripheral blood of this teenager and his father by genetic testing, which encoded a desmosomal protein that was related to arrhythmogenic right ventricular cardiomyopathy (ARVC). In these two rare variants, DSC2 V816M has been reported but uncertain significance, whereas DSP R1207K is never reported. Therefore, the two site variants in DSC2 and DSP genes are likely to become a new research focus for diagnosis and treatment of ARVC in the future. Meanwhile, this report emphasizes that, in addition to a standard set of laboratory tests and examinations, genetic testing may be useful for analyzing the causes of malignant arrhythmia.


Assuntos
Arritmias Cardíacas/etiologia , Bloqueio de Ramo/genética , Desmocolinas/genética , Eletrocardiografia/métodos , Predisposição Genética para Doença , Adolescente , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Bloqueio de Ramo/complicações , Bloqueio de Ramo/diagnóstico , Ecocardiografia/métodos , Testes Genéticos/métodos , Humanos , Masculino , Linhagem , Prognóstico , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença
10.
Zhonghua Er Ke Za Zhi ; 57(9): 674-679, 2019 Sep 02.
Artigo em Chinês | MEDLINE | ID: mdl-31530352

RESUMO

Objective: To examine genetic variants of familial hematuria (FH) associated genes in 3 families with hematuria with probands initially diagnosed with IgA nephropathy (IgAN). Methods: A retrospective analysis was performed on the clinical data, laboratory tests and genetic test results of three children with hematuria and the probands in three families with hematuria. The families were ascertained at the Department of Pediatrics, Fuzhou General Hospital of Nanjing Military Command from August 2014 to May 2018. Results: The proband of Family One, an 8-year-old boy, manifested gross hematuria. His renal biopsy pathology revealed IgAN. His father also manifested hematuria. Genetic testing showed that the proband and his father carried a heterozygous variant of the CFHR5 gene,533A>G (Asn178Ser). The child of Family Two, a 4-year-old girl, manifested hematuria. Her father, the proband of the family, was 36 years old, and manifested hematuria, proteinuria, high-frequency sensorineural deafness and renal insufficiency. He was diagnosed as IgAN according to clinical manifestations, renal pathology and routine immunohistochemistry without renal biopsy electron microscopy, renal tissue type Ⅳ collagen α3, α4, α5 chains immunofluorescence and skin type Ⅳ collagen α5 chain immunofluorescence. Genetic testing showed that the girl carried a heterozygous variant of the COL4A5 gene,566G>T (Gly189Val), and her father carried the hemizygous variant. The child of Family Three, a 7-year-old girl, manifested hematuria and proteinuria. Her mother, the proband of the family, was 34 years old, and manifested hematuria and proteinuria as well. The proband was diagnosed as IgAN by the same method used for Family Two. The girl's grandfather died of uremia at the age of 44. Genetic testing showed that the girl and her mother carried a heterozygous variant 539G>A (Gly180Glu)in COL4A5 gene. Conclusions: The variant of the CFHR5 gene identified in Family One is of uncertain signifance, and the two variants of the COL4A5 gene identified in Families Two and Three are pathogenic. The probands of Families Two and Three are diagnosed as Alport syndrome. The study suggests that clinicians should examine genetic variants of FH associated genes in families with hematuria when the probands were diagnosed as IgAN by their clinical manifestations, renal pathology and routine immunohistochemistry.


Assuntos
Variação Genética/genética , Hematúria/diagnóstico , Nefrite Hereditária/diagnóstico , Adulto , Criança , Pré-Escolar , Feminino , Testes Genéticos/métodos , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Hematúria/genética , Humanos , Rim , Masculino , Nefrite Hereditária/genética , Estudos Retrospectivos , Sequenciamento Completo do Exoma
12.
Phys Chem Chem Phys ; 21(37): 20678-20692, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31508628

RESUMO

In this work we present a high-throughput approach to the computation of absorption UV-Vis spectra tailored to mutagenesis studies. The scheme makes use of a single molecular dynamics trajectory of a reference (non-mutated) species. The shifts in absorption energy caused by a residue mutation are evaluated by building an effective potential of the environment and computing a correction term based on perturbation theory. The sampling is only performed in the phase space of the initial protein. We analyze the robustness of the method by comparing different approximations for the effective potential, the sampling of mutant residue geometries and observing the impact in the prediction of both bathocromic and hypsochromic shifts. As a test subject, we consider a red fluorescent protein variant with potential biotechnological applications.


Assuntos
Testes Genéticos/métodos , Luz , Proteínas/química , Proteínas/genética , Análise Espectral , Raios Ultravioleta , Simulação de Dinâmica Molecular , Mutação
13.
Microbiol Res ; 228: 126306, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31422233

RESUMO

The mariner transposon family of Himar1 has been widely used for the random mutagenesis of bacteria to generate single insertions into the chromosome. Here, a versatile toolbox of mariner transposon derivatives was generated and applied to the functional genomics investigation of fish pathogen Edwardsiella piscicida. In this study, we combined the merits of the random mutagenesis of mariner transposon and common efficient reporter marker genes or regulatory elements, mCherry, gfp, luxAB, lacZ, sacBR, and PBAD and antibiotic resistance cassettes to construct a series of derivative transposon vectors, pMmch, pMKGR, pMCGR, pMXKGR, pMLKGR, pMSGR, and pMPR, based on the initial transposon pMar2xT7. The function and effectiveness of the modified transposons were verified by introducing them into E. piscicida EIB202. Based on the toolbox, a transposon insertion mutant library containing approximately 3.0 × 105 distinct mutants was constructed to explore the upstream regulators of esrB, the master regulator of the type III and type VI secretion systems (T3/T6SS) in E. piscicida. Following analysis by Con-ARTIST, ETAE_3474, annotated as fabR and involved in fatty acid metabolism, was screened out and identified as a novel regulator mediating T3SS and T6SS expression. In addition, the fabR mutants displayed critical virulence attenuation in turbot. Due to the broad-range host compatibility of mariner transposons, the newly built transposon toolbox can be applied for functional genomics studies in various bacteria.


Assuntos
Proteínas de Bactérias/genética , Elementos de DNA Transponíveis , Edwardsiella/genética , Regulação Bacteriana da Expressão Gênica/genética , Testes Genéticos/métodos , Genoma Bacteriano/genética , Animais , Mapeamento Cromossômico , Farmacorresistência Bacteriana/genética , Ácidos Graxos/metabolismo , Doenças dos Peixes/microbiologia , Biblioteca Gênica , Genes Reporter/genética , Genômica/métodos , Mutagênese Insercional/métodos , Fatores de Transcrição/genética , Sistemas de Secreção Tipo III/genética , Sistemas de Secreção Tipo VI/genética , Virulência , Fatores de Virulência/genética
14.
Arch Endocrinol Metab ; 63(4): 369-375, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365623

RESUMO

OBJECTIVE: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. RESULTS: We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. CONCLUSIONS: PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Mutação em Linhagem Germinativa/genética , Paraganglioma/genética , Feocromocitoma/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Masculino , Linhagem , Estudos Retrospectivos , Vigilância de Evento Sentinela
15.
Medicine (Baltimore) ; 98(30): e16566, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348283

RESUMO

RATIONALE: Cardiac transthyretin amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of clinical manifestations, routine electrocardiogram, echocardiography and the traditional requirement for endomyocardial biopsy confirmation. PATIENT CONCERNS: A 68-year-old female had suffered from lumbago for 5 years with progressive weakness, numbness in both lower limb. DIAGNOSIS: The patient's clinical signs were not specific, but cardiac amyloidosis was suspected based on relative left ventricular apical sparing of longitudinal strain on echocardiography and continuous elevated serum levels of cardiac biomarkers (ultrasensitive cardiac troponin I and NT-proBNP). She was finally diagnosed hereditary transthyretin-related cardiac amylodosis by specific findings of cardiovascular magnetic resonance imaging (CMR), -technetium pyrophosphate (Tc-PYP) scintigraphy and genetic testing. INTERVENTIONS: The patient received medications including diuretics, beta-blockers and angiotensin-converting enzyme inhibitors at the time of hospitalization. Ultimately, however, she refused further treatments and requested discharge from our hospital. OUTCOMES: A series of noninvasive technique enables the diagnosis of hereditary transthyretin-related cardiac amyloidosis. LESSONS: While endomyocardial biopsy is not able to performed, this case demonstrates that a combination of noninvasive techniques, especially CMR, nuclear imaging, and genetic testing, may help us to make a correct diagnosis of hereditary transthyretin-related cardiac amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Técnicas de Imagem Cardíaca/métodos , Testes Genéticos/métodos , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina I/sangue , Idoso , Ecocardiografia/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Cintilografia/métodos , Compostos Radiofarmacêuticos , Pirofosfato de Tecnécio Tc 99m
17.
Med Oncol ; 36(8): 71, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270633

RESUMO

BRCA1 is involved in double-strand DNA damage repair pathways, and mutations in the gene are associated with hereditary breast and ovarian cancers. With great help of the development of high-throughput DNA sequencing techniques numerous single-nucleotide polymorphisms (SNPs) and insertion deletion (Indel) mutations are detected on both coding and non-coding/regulatory regions of the BRCA1. Mutations may cause pathogenic or benign changes on the protein function or affect its expression. In the last decade, use of genetic screening tests to detect mutations on such genes has become greatly popular. However, it is very important to know the effect of the detected mutations, which is mostly possible by the use of predictive softwares, and also the related family history to be able to correctly analyse the screening results and to inform the patient. Therefore, use of in silico and in vitro techniques to score the pathogenicity of detected variants on genes like BRCA1 is now of great importance. Otherwise, results obtained from screening tests and family history cannot be analysed precisely.


Assuntos
Proteína BRCA1/genética , Genes BRCA1 , Testes Genéticos/métodos , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Neoplasias da Mama/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único
18.
BMC Med ; 17(1): 132, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31291970

RESUMO

BACKGROUND: Monogenic diabetes (MgD) accounts for 1-2% of all diabetes cases. In adults, MgD is difficult to distinguish from common diabetes causes. We assessed the diagnosis rate and genetic spectrum of MgD using next-generation sequencing in patients with late adolescence/adult-onset diabetes referred for a clinical suspicion of MgD. METHODS: This cross-sectional study was performed in 1564 probands recruited in 116 Endocrinology departments. Inclusion criteria were the absence of diabetes autoantibodies, and at least two of the three following criteria: an age ≤ 40 years and a body mass index (BMI) < 30 kg/m2 at diagnosis in the proband or in at least two relatives with diabetes, and a family history of diabetes in ≥ 2 generations. Seven genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, KCNJ11, and INS) were analyzed. Variant pathogenicity was assessed using current guidelines. RESULTS: Pathogenic variants were identified in 254 patients (16.2%) and in 23.2% of EuroCaucasian patients. Using more stringent selection criteria (family history of diabetes in ≥ 3 generations, age at diabetes ≤ 40 years and BMI < 30 kg/m2 in the proband, EuroCaucasian origin) increased the diagnosis rate to 43%, but with 70% of the identified cases being missed. GCK (44%), HNF1A (33%), and HNF4A (10%) accounted for the majority of the cases. HNF1B (6%), ABCC8/KCNJ11 (4.4%), and INS (2.8%) variants accounted for 13% of the cases. As compared to non-monogenic cases, a younger age, a lower BMI and the absence of diabetes symptoms at diagnosis, a EuroCaucasian origin, and a family history of diabetes in ≥ 3 generations were associated with MgD, but with wide phenotype overlaps between the two groups. In the total population, two clusters were identified, that mainly differed by the severity of diabetes at onset. MgDs were more prevalent in the milder phenotypic cluster. The phenotypes of the 59 patients (3.8%) with variants of uncertain significance were different from that of patients with pathogenic variants, but not from that of non-monogenic patients. CONCLUSION: Variants of HNF1B and the K-ATP channel genes were more frequently involved in MgD than previously reported. Phenotype overlapping makes the diagnosis of MgD difficult in adolescents/adults and underlies the benefit of NGS in clinically selected patients.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Adulto Jovem
19.
Nat Commun ; 10(1): 2985, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278258

RESUMO

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.


Assuntos
Deficiências do Desenvolvimento/genética , Exoma/genética , Mosaicismo , Sequenciamento Completo do Exoma/métodos , Criança , Estudos de Coortes , Deficiências do Desenvolvimento/diagnóstico , Feminino , Testes Genéticos/métodos , Variação Genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Herança Materna/genética , Pais , Herança Paterna/genética
20.
Genome Biol ; 20(1): 132, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262344

RESUMO

CRISPR-based nucleic acid detection methods are reported to facilitate rapid and sensitive DNA detection. However, precise DNA detection at the single-base resolution and its wide applications including high-fidelity SNP genotyping remain to be explored. Here we develop a Cas12b-mediated DNA detection (CDetection) strategy, which shows higher sensitivity on examined targets compared with the previously reported Cas12a-based detection platform. Moreover, we show that CDetection can distinguish differences at the single-base level upon combining the optimized tuned guide RNA (tgRNA). Therefore, our findings highlight the high sensitivity and accuracy of CDetection, which provides an efficient and highly practical platform for DNA detection.


Assuntos
Sistemas CRISPR-Cas , DNA/análise , Técnicas Genéticas , Testes Genéticos/métodos , Escherichia coli , Humanos , Sensibilidade e Especificidade
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